6-alkoxy - 16 - alkylidene - 17alpha - lower alkanoyloxy-21-desoxy - 4 6 - pregnadienes methods for their manufacture and intermediates produced thereby

ABSTRACT

6-ALKOXY-16-LOWER ALKYLIDENE-17A-LOWER ALKANOYLOXY4,6-PREGNADIENE-3,20-DIONES AND 1A,2A-CYCLOMETHYLENE DERIVATIVES THEREOF HAVING PROGESTATIONAL AND ANTI-ANDROGENIC ACTIVITY ARE PREPARED BY TREATING A 6-KETO-16-LOWER ALKYLIDENE-17A-LOWER ALKANOLYOXY-4-PREGNANE-3,20-DIONE WITH BORON TRIFLUORIDE IS A LOWER ALKANOL. PREFERRED COMPOUNDS ARE 6-METHOXY-16-LOWER ALKYLDENE-17A-LOWER ALKANOYLOXY-4,6-PREGNADIENE-3,20-DIONE WITH BORON TRIFLUORIDE IS A LOWER ALKANOL. PREFERRED COMPOUNDS ARE 6-METHOXY-16-LOWER ALKYLIDENE-17A-LOWER ALKANOYLOXY-4,6-PREGNADIENE-3,20-DIONES (PARTICULARLY 6-METHOXY-16-METHYLENE-17A-ACETOXY-4,6PREGNADIENE-3,20-DIONE) AND THEIR 1A,2A-CYCLOMETHYLENE DERIVATIVES, WHICH ARE VALUABLE IN THE TREATMENT OF BENIGN PROSTATIC HYPERTROPHY. THESE 6-METHOXY COMPOUNS ARE ALSO PREPARED BY REACTION OF A 16-LOWER ALKYLIDENE-17ALOWER ALKANOYLOXY-4-PREGNENE-3,20-DIONE OR A 3-ENOL ETHER OR 3-ENOL ESTER DERIVATIVE THEREOF WITH A CUPRIC HALIDE IN METHANOL. THE 1A,2A-CYCLOMETHYLENE-6-ALKOXY-16-LOWER ALKYLIDENE-17A-LOWER ALKANOYLOXY-4,6-PREGNADIENE-3,20-DIONES ARE ALSO PREPARED FROM A 6-ALKOXY-16-LOWER ALKYLIDENE17A-LOWER ALKANOYLOXY-1,4,6-PREGNATRIENE-3,20-DIONE BY REACTION WITH DIMETHYLSULFOXONIUM METHYLIDE.

United States Patent 3,629,303 fi-ALKOXY 16 ALKYLIDENE 17oz LOWER ALKANOYLOXY-Zl-DESOXY 4,6 PREGNA- DIENES, METHODS FOR THEKR MANUFAC- TURE AND INTERMEDIATES PRODUCED THEREBY Richard Rausser, Union, and Robert Tiheri, Englishtown, N.J., assignors to Schering Corporation, Bloomfield,

Nb'nrawin Filed June 9, 1969, Ser. No. 831,739 1m. on. can 169/34 US. Cl. 260397.4 26 Claims ABSTRACT OF THE DISCLOSURE 6 alkoxy-l6-lower alkylidene-l7a-lower alkanoyloxy- 4,6 pregnadiene 3,20-diones and la,2u-cyclomethylene derivatives thereof having progestational and anti-androgenic activity are prepared by treating a 6-keto-l6-lower alkylidene l'7a-lower alkanolyoxy-4-pregnane-3,ZO-dione with boron trifluoride is a lower alkanol.

Preferred compounds are 6-meth0xy-l6-lower alkylidene l7a-lower alkanoyloxy-4,6-pregnadiene-3,ZO-diones (particularly 6-methoxy-l6 methylene-l7a-acetoxy-4,6- pregnadiene-3,20-dione) and their 1a,2a-cyclomethylene derivatives, which are valuable in the treatment of benign prostatic hypertrophy. These o-methoxy compounds are also prepared by reaction of a 16-lower alkylidene-l7alower al-kanoyloxy-4-pregnene-3,20 dione or a 3-enol ether or 3-enol ester derivative thereof with a cupric halide in methanol.

The 104,20 cyclomethylene-6-alkoxy-l6-1ower alkylidene l7a-lower alkanoyloxy-4,6-pregnadiene-3,20-diones are also prepared from a 6-alkoXy-l6-lower alkylidenel7a-lower al-kanoyloxy-1,4,6-pregnatriene-3,ZO-dione by reaction with dimethylsulfoxonium methylide.

FIELD OF INVENTION This invention relates to compositions of matter which may be classified as 6-lower alkoxy-lower alkylidene- 17u-10WB1 alkanoyloXy-6-dehydro derivatives of steroids of the progesterone series, to methods for their manufacture, and to intermediates produced thereby.

SUMMARY OF INVENTION The invention sought to be patented in the first composition of matter aspect resides in the concept of a steroid of the progesterone series which has an additional double bond between C6 and C-7 and 6-lower alkoxyl6-lower alkylidene-l7a-lower alkanoyloxy substituents, said steroids possessing progestational and anti-androgenic activity. A preferred species of this aspect of our invention are 6-methoxy-l6-methylene-21-unsubstituted pregnane derivatives, praticularly 6-methoXy-16'methylene- 17a-acetoXy-4,6-pregnadiene-3,ZO-dione, which demonstrates high anti-androgenic activity in tests in the rat and in dogs and is valuable as a therapeutic agent for use in the treatment of benign prostatic hypertrophy.

The invention sought to be patented in a second composition-of-matter aspect resides in the concept of steroids of the 6-dehydroprogesterone series and of the 1,6-bisdehydroprogesterone series which have 6-lower alkoxyl6-lower alkylidene-l7a-hydroxy substituents, as well as steroids of the 1,6-bis-dehydroprogesterone series having 6-lower alkoxy-lG-lower alkylidene-lh-lower alkanoyloxy substituents, all of said compounds, being valuable as intermediates in the preparation of the therapeutically valuable compounds of the first composition of matter aspect of our invention.

The invention sought to be patented in a third composition of matter aspect resides in the concept of 6- keto-l6-lower alkylidene-lh-lower alkanoyloxy progesterones which are valuable as intermediates in preparing 6-flikOXY-16-1OW6I alkylidene-lh-lower alkanoyloxy 6-dehydroprogesterones of our invention.

There are also three process aspects of this invention. Of these, the invention sought to be patented in the first process aspect resides in the concept of preparing 6- methoxy-16-lower alkylidene-lh-lower alkanoyloXy-4,6- pregnadiene-3,20-diones (i.e. 6-methoxy-l6-lower a1- kylidene-lh-lower alkanoyloxy-6-dehydrogrogesterones) by treatment of a member of the group consisting of a l6-lower alkylidene-l7a-lower alkanoyloXy-4-pregnene-3, 20-dione having saturated carbons at C-6 and C-7, a 3- enol lower alkoxy derivative thereof, and a 3-enol lower alkanoyloxy derivative thereof, in methanol, with a cupric halide of the group consisting of cupric bromide and cupric chloride.

A preferred species of this process is that wherein the starting steroid is a 16-lower alkylidene-lh-lower alkanoyloXy-4-pregnene-3,20-dione, particularly 16-methylene-17a-acetoxyprogesterone, whereby is prepared the preferred species of the first composition of matter aspect of this invention, i.e. 6-methoxy-16-methylene-17uacetoxy-o-dehydroprogesterone,

The invention sought to be patented in a second process aspect of this invention resides in the concept of treating a 6-keto-l6-lower a1kylidene-17a-lower alkanoyloxy- 4-pregnene-3,20-dione in a lower alkanol with an acid catalyst such as mineral acids, p-toluenesulfonic acid, and, preferably, borontrlfluoride whereby is formed a 6-lower alkoXy-l6-lower alkylidene-l7a-l0wer alkanoyloXy-4,6-pregnadiene-3,20-dione.

A preferred species of this process is that wherein the 6-keto-16 lower alkylidene-lh-lower alkanoyloxy-4- pregnene-3,20-dione starting compound is prepared from a 6-methoxy-16-lower alkylidene-lh-lower alkanoyloxy- 4,6-pregnadiene-3,20-dione of this invention by acid hydrolysis, i.e, by treatment with such as hydrogen chloride, hydrogen bromide, sulfosalicylic acid, and p-toluenesulfonic acid in aqueous acetic acid as solvent. The second process aspect of our invention thus provides a convenient method of preparing higher 6-al koxy analogs of our invention, e.g. 6-ethoxy derivatives, from the corresponding 6-methoxy compounds.

A third process aspect of this invention resides in the concept of preparing lu,2a-cyclomethylene 6 lower alkoXy-16-lower alkylidene-17u-hydroxy-4,6-pregnadiene- 3,20-diones and the 17-lower alkanoic acid esters thereof by treating a member selected from the group consisting of 6-lower alkoxy-16-lower alkylidene-17u-hydroxy-1,4,6- pregnatriene-3,20-diones and the 17-1ower alkanoic acid esters thereof with a methylene transfer agent, e.g. dimethylsulfoxonium methylide prepared in situ by reaction of trimethylsulfoxonium iodide with sodium hydride in dimethylsulfoxide.

3 GENERAL DESCRIPTION OF THE INVENTION First composition of matter aspect The first composition of matter aspect of our invention (LRI wherein R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine, and chlorine; Y is lower alkanoyloxy; and Z is a member selected from the group consisting of By the term lower alkyl is contemplated hydrocarbon radicals having preferably up to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, and t-butyl, although higher homologs such as pentyl and hexyl come within the scope of this invention.

The term lower alkanoyloxy is contemplated as including hydrocarbon carboxylic acid radicals of lower alkanoic acids having preferably up to eight carbon atoms such as radicals obtained from acetic, propionic, valeric, caprylic, caproic, t-butyl-acetic acid and the like.

Our invention thus includes 6-lower alkoxy-16-lower alkylidene-lh-lower alkanoyloxy-6-dehydroprogesterones unsubstituted at C1 and C-2 (i.e. compounds of Formula I wherein Z is CH CH such as:

and also includes 1a,2a-cyclomethylene-6-alkoxy-16-lower alkylidene-6-dehydroprogesterones (i.e. compounds of Formula I wherein Z is on, -on-cn la,2a-cyclomethylene-6-methoxy-l6-methylene-17aacetoxy-4,6-pregnadiene-3 ,ZO-dione, 1a,2a-cyclomethylene-6-ethoxy-16-methylene-17aacetoxy-4,6-pregnadiene-3 ,20dione, 1a,2a-cyclomethylene=6-methoxyl 6-rnethylene- 1 7aacetoxy-2l-fiuoro-4,6-pregnadiene-3,20-dione; and 1a,2a-cyclomethylene-6-methoxy-16-methylene-17avaleroxy-4,6-pregnadiene-3,20-dione.

exemplified by The new compounds defined by Formula I possess valuable pharmacological and therapeutic properties and may be used as medicaments in conditions requiring a progestational agent, eg. in fertility control and in the manage ment of various menstrual disorders. They may be administered via the oral or intramuscular route in a manner similar to that in which known progestational agents, e.g. progesterone, are administered, the dosage depending on the age and size of the patient and in the nature and severity of the ailment being treated. The progestational activity of compounds of Formula I was demonstrated in studies in immature rats by the well known Clauberg method via the oral and intramuscular route. For example, in this test, 6 methoxy-l6-methylene-l7a-acetoxy-4,6- pregnadiene-3,20-dione is about six times as active as progesterone via the oral route and about 14 times as active as progesterone via the intramuscular route.

Our new compounds -find their greatest use in the treatment of disorders requiring anti-androgen therapy such as in the treatment of acne, or benign prostatic hypertrophy. The anti-androgenic activity of compounds of Formula I was studied in the intact male immature rat by the test described by R. O. Neri et al., Eur. J. Pharm. 1, 438-444 (1967) (Section 2.1.2, p. 439). It was demonstrated that at 10 mgm./kgm. doses administered subcutaneously in sesame oil, anti-androgenic activity was exhibited by compounds of Formula I such as 6-methoxy- 16-methylene 17oz acetoxy-4,6-pregnadiene-3,20-dione, 6 ethoxy l6 methylene-17ot-acetoxy-4,6-pregnadiene- 3,20 dione, and 111,20; cyclomethylene-6-methoxy-1-6- methylene-l7a-acetoxy-4,6-pregnadiene-3,20 dione. The anti-androgenic activity of 6-alkoxy-16-alkylidene-17alower alkanoyloxy 6 dehydroprogesterones was also studied in orchiectomized rats by the test described by R. O. Neri et al., Eur. J. Pharm. 1, 438-444 (1967) (Section 2.1.1, page 438). It was found, for example, that at 25 mgm./kg. doses administered subcutaneously to orchiectomized rats, 6 methoxy 16 methylene 170cacetoxy-4,6-pregnadiene-3,ZO-clione inhibited the testosterone (50 m induced hypertrophy of the secondary sex structures, thus exhibiting anti-androgenic activity. The anti-androgenic activity of compounds of Formula I is also demonstrated by results of studies in old male dogs having hyperplastic prostates by the method described by R. O. Neri et al., Endocrinology 82, 311 (1968). It was found, for example, when 6-methoxy-16- methylene-l7a-acetoxy-4,6-pregnadiene 3,20 dione was injected intramuscularly at 5 mg./kg. doses daily for six weeks or was administered orally at 15 mgm./kg. doses daily for six weeks, to dogs having prostatic hyperplasia, that prostatic volumes and epithelial cell heights were reduced and that the acid phosphatase and protein content of the hyperplastic prostate were also reduced and the symptoms of prostatic hyperplasia alleviated.

Our compounds are most valuable for use in the treatment of benign prostatic hypertrophy which occurs spontaneously in man as well as in dogs. Of the compounds of Formula I, a preferred species for the treatment of benign prostatic hypertrophy is 6-methoxy-l6-methylene-l7alower alkanoyloxy-4,G-pregnadiene-3,20-dione.

When treating a male mammal, e.g. a dog, having benign prostatic hypertrophy, the active compounds of Formula I of this invention can be administered orally in the form of tablets, capsules, elixirs and the like or may be administered by parenteral injection. In tablet form they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, gums, starches and sugars. They may also be incorporated into gelatin capsules or formulated into elixirs which have the advantage of being susceptible to manipulations in flavor by the addition of standard natural or synthetic flavoring agents. Highly satisfactory administration may also be achieved in the form of aqueous parenteral suspensions. Preferably, these formulations are so proportioned as to afiord a unit dosage of from about 1 to about mg. of active ester. Particularly preferred are unit dosages ranging from about 5 to about 25 mg.

Typical formulations incorporating the active 6-alkoxyl6-lower alkylidene-l7ot-lower alkanoyloxy-G-dehydroprogesterone of this invention are described hereinbelow as Formulations I to III.

In order to achieve a satisfactory response in the treatment and control of benign prostatic hypertrophy with, for example, 6-methoxy-l6-methylene-17u-acetoXy-4,6- pregnadiene-3,20-dione, it is necessary to administer daily 1 to 4 tablets or capsules having from about 1 to about 100 mgm. unit doses. The usual injection dosage is 1 to 4 ml. per day comprising a total daily dosage of from about 0.5 to 50 mgm. In severe or aggravated conditions additional medication may be administered.

Second composition of matter aspect The invention sought to be patented in the second comsition of matter aspect includes compounds defined by the following structural Formula II which are valuable, mainly as intermediates in the third process aspect of this invention.

wherein R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine and chlorine; and Z is a member selected from the group consisting of CH CH CH=CH, and

E -ort onand when Z is -CH CH, the 170t-1OW81' alkanoate esters thereof.

The compounds of Formula II thus include 17 a-hydroxy precursors of the l7a-lower alkanoate therapeutically valuable compounds of our invention (Formula I hereinabove) such as 6-methoxy-l6-methylene-l7a-hydroxy-4,6-pregnadiene- 3 ,20-dione,

6-methoxy-16-ethylidene-17a-hydroxy-4,6-pregnadiene- 3,20-dione, and

1(2,2a-cyclomethylene-6-methoxy-1G-methylene-17ahydroxy-4,6-pregnadiene-3,20-dione.

The 17oc-hYdIOXY intermediates of Formula II are easily converted to the corresponding 17oc-1OW6I alkanoates of Formula I having anti-androgenic activity when treated according to known methods for esterifying tertiary alcohols. Thus, for example, 6-methoxy-l6-methylene-17a-hydroxy-4,6-pregnadiene-3,ZO-dione upon treatment with acetic acid in the presence of p-toluenesulfonic acid and trifluoroacetic anhydride yields 6-methoxy-16-methylene- 17 ot-acetoxy-4,6-pregnadiene-3,20-dione.

The l-dehydro compounds defined by Formula II are also valuable as intermediates in the third process aspect of this invention whereby are prepared pharmacologically active lot,2u-cyclomethylene derivatives of the 6-loWer alkoXy-lG-lower alkylidene-l7a-lower alkanoyl-6-dehydroprogesterones defined by Formula I hereinabove.

The compounds of Formula II are derived from known 16-lower alkylidene-17u-hydroxyprogesterones via the first process aspect of this invention or from the corresponding 17a-lOW6l alkanoates via alkaline hydrolysis.

Third composition of matter aspect The invention sought to be patented in the third composition-of-matter aspect includes 6-keto-16-lower alkylidene 17a-lower alkanoylprogesterones as defined by Formula III.

wherein R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consist-ing of hydrogen, fluorine, and chlorine; Y is lower alkanoyl; and Z is a member selected from the group consisting of CH CH -'CH=CH, and

GENERAL DESCRIPTION OF THE PROCESS ASPECTS OF THIS INVENTION First process aspect By the first process aspect of this invention are prepared 6-methoxy-pregnanes of the first and second product aspects of this invention, i.e. compounds having the following structural Formula IV:

OCH

wherein R is a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consisting of hydrogen, fluorine and chlorine; Y is a member selected from the group consisting of hydroxy and lower alkanoyloxy; and Z is a member selected from the group consisting of CH -CH CH=CH, and

which comprises treatment of a member selected from the group consisting of 16-alkylidene progesterones of the following Formula V and the 3-enol ethers and the 3- enol esters thereof of Formula VI:

Z. OF

wherein R X, Y and Z are as hereinabove defined and V is a member selected from the group consisting of lower alkyl and lower alkanoyl, with a reagent selected from the group consisting of cupric chloride and cupric bromide in methanol.

In carrying out the physical embodiment of our process whereby 6-unsubstituted-l6-alkylidene-Not-oxygenated progesterones or the 3-enol ethers or 3-enol esters thereof are converted to the corresponding 6-methoxy-16- alkylidene-l7a-oxygenated-6-dehydro progesterones, it is preferable to use anhydrous methanol which can serve as solvent and/or diluent as well as reagent. For optimum results, about four moles of the cupric halide reagent is required per mole of 16-alkylidene-progesterone starting steroid or of the enol-ether or enol-ester thereof. Usually, from about 4 to about 4.4 moles of cupric chloride or cupric bromide may be used per mole of starting steroid; we have found that maximum yields are obtained when 4 moles of the cupric halide is used per mole of starting steroid.

Our process may be carried out at temperatures in the range of from about 5 C. up to about the reflux temperature of methanol (i.e. about 65 C.), preferably at methanol reflux temperature. The reaction time is dependent upon the temperature at which our process is carried out. When our process is run at about 65 C., the reaction is usually completed within a period from one-half hour to about one and a half hours. When carrying out our process at 5 C., it will be several days before complete conversion of the 6-unsubstituted progesterone to a 6-methoxy- 6-dehydroprogesterone is effected.

The 6-methoxy 16 alkylidene-17a-hydroxy (or alkanoyloxy)-6-dehydroprogesterone product of this process is isolated and purified by utilizing known procedures including solvent extraction, filtration, crystallization, chromatographic techniques, and the like.

In a preferred mode of the physical embodiment of this aspect of our invention, 16-methylene-l7ot-acetoxy- 4-pregnene-3,20-di0ne (i.e. 16-methylene-l7ot-acetoxyprogesterone) suspended in methanol is reacted with about 4 moles of cupric chloride hydrate for about one hour at reflux temperature (i.e. at about 65 C.). After filtering the reaction mixture, the resulting product is isolated by adding the reaction mixture (after being concentrated to about a fourth of its original volume) to saturated aqueous ammonium chloride, then filtering the resulting precipitate of 6-methoxy-l6-methylene-l7aacetoxy-6-dehydroprogesterone. Purification is usually effected by recrystallization.

Advantageously, our process may also utilize as starting compounds either enol ether or enol ester derivatives of 16-alkylidene-17a-hydroxy (or alkanoyloxy) progesterones. When these enol derivatives are utilized as starting compounds, our process is carried out in the same manner as when utilizing a 3-keto starting steroid and there will be isolated the desired 6-methoXy-6-dehydroprogesterone.

The 16-alkylidene-l7a-hydroxy (or alkanoyloxy) progesterone starting compounds of this process aspect are either known in the art or can be prepared by known methods. The starting l6-alkylidene-progesterones of Formula IV wherein Z is --CH CH or CH=CH- are described in, or prepared by, processes described in US. Pat. No. 3,312,692. The compounds of Formula 1V wherein Z is 5 o'rrcrrare known; if unavailable, they can be prepared from the l-dehydro compounds of Formula IV by treatment with dimethylsulfoxonium methylide prepared from trimethylsulfoxonium iodide and sodium hydride in dirnethylsulfoxide in a manner similar to that described hereinbelow. process aspect of our invention described hereinbelow.

The 3-enol ether and 3-enol ester starting derivatives are prepared from the corresponding progesterone utilizing known methods. Thus, the ethyl enol ether of 16- methylene 17a acetoxyprogesterone (i.e. 3-ethoxy-l6- methylene-17a-acetoxy 3,5 pregnadien-ZO-one) is prepared by reaction of the progesterone with ethyl-o-formate, concentrated sulfuric acid, anhydrous ethanol and dioxane. Similarly, the 3-acetoxy enol ester of l6-meth'ylene a acetoxyprogesterone (i.e., 3,l7o-diacetoxy-16 methylene-3,S-pregnadien-ZO-one) is prepared by reaction of the progesterone with sulfosalicylic acid and acetic anhydride in toluene.

Second process aspect 1 The second process aspect of our invention resides in the concept of treating a 6-keto-l6-alkylidene-l7a-oxygenated progesterone of structural Formula III (described hereinabove) with boron trifluoride in a lower alkanol whereby is prepared a 6-alkoxy-16-alkylidene- 17OL-1OW6I' alkanoyloxy-6-dehydroprogesterone of the following structural Formula VII:

wherein R is a lower alkyl, R is a member selected from the group consisting of hydrogen and lower alkanoyl; X is a member selected from the group consisting of hydrogen, fluorine and chlorine; Y is lower alkanoyloxy; and Z is a member selected from the group consisting of CH --CH -C'H=CH, and

5 o'n:orr-

Conversion of a 6-keto-l6-alkylideneprogesterone, III, to a 6-alkoxy-l6-alkylidene-l7u-lower alkanoyl-6-dehydroprogesterone, VII, is effected by treating the 6-ketoprogesterone with an excess of boron trifluoride in a lower alkanol at room temperature for about 48 hours to obtain a 6-alkoxy derivative corresponding to the alkanol used in the process, e.g. when ethanol is the solvent used, a 6-ethoxy-6-dehydroprogesterone of Formula VII is formed; and when isopropanol is the alcohol used, a 6-isopropoxy-6-dehydroprogesterone is formed. The resultant 6-alkoxy derivative of Formula VII is easily isolated by adding the reaction mixture to aqueous sodium bicarbonate solution and filtering the resultant precipitate. Purification can be effected by known methods, including recrystallization, chromatography and the like.

A convenient method of preparing the necessary 6keto starting compounds of Formula III, is by converting a 6-methoxy compound of Formula 1V (prepared by the first process aspect of our invention) via acid catalyzed hydrolysis employing mineral acids or, preferably, by treatment with p-toluenesulfonic acid in 80% acetic acid. Usually to prepare a 6-keto compound of Formula III from a 6-methoxy-derivative of Formula IV, to 6-methoxy-l6-alkylidene-6-dehydroprogesterone of Formula IV there is added p-toluenesulfonic acid in 80% acetic acid and the reaction is carried out at reflux temperature for about one hour. Isolation and purification of the resulting 6-keto-16-alkylidene product is conveniently effected by adding Water to the reaction mixture, filtering the resultant precipitate, and purifying via precipitation or chromatographic techniques.

The second process aspect of our invention thus provides a method of converting the 6-methoxy-16-alkylidene-6-dehydroprogesterones of our invention to higher 6-alkoxy homologs thereof. A preferred species of the second process aspect of this invention is the preparation of 6 ethoxy-l6-methylene-l7a-acetoxy-4,6-pregnadiene- 3,20-dione from 6 keto l6 methylene-l7a-acetoxy-4- pregnene-3,20-dione derived from 6-methoxy-l6-methylene-l7a-acetoxy-4,6-pregnadiene-3,20-dione as specifically described in Example 9 herein.

Third process aspect A preferred method of preparing the 10L,2OL-CyClOlI1ethylene compounds of our invention, i.e. those compounds of Formulae I and II wherein Z or Z is having the following Formula VLIII:

CH X

o=o L CHR1 re OR VIII wherein R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, chlorine and fluorine; and Y is a member selected from the group consisting of hydroxy and lower alkanoyloxy; comprises treating a l-dehydro compound of our invention (i.e. those compounds of Formula II wherein Z is CI-I CH) of the following Formula IX:

wherein R, R X and Y are as defined hereinabove for Formula VIII; with about a molar equivalent of dimethylsulfoxonium methylide prepared from two molar equivalents of trimethylsulfoxonium iodide and about one molar equivalent of sodium hydride per mole steroid in dimethylsulfoxide.

The physical embodiment of this aspect of our invention is usually carried out under an inert atmosphere, e.g. argon gas, at room temperature, e.g. in the temperature range of about 10 C. to about 25 C., for a period of about 20 to 24 hours.

A preferred species of this process aspect of our invention is the preparation of lu,2a-cyclo1nethylene-6- methoxy-16-methylene-l7a-acetoxy-4,6-pregnadiene-3,20- dione (i.e. a compound of Formulae I and VIII wherein R is methyl, X and R are hydrogen and Y and Y are acetoxy) from 6-methoxy-l6-methylene-17ot-hydroXy-1,4, 6-pregnatriene-3,20-dione (a compound of Formula IX wherein R is methyl, R and X are hydrogen, and Y is hydroxy) by treatment with dimethylsulfoxonium methylide prepared by reaction of trimethylsulfoxonium iodide and sodium hydride under an atmosphere of argon as specifically described in Example 7A followed by acetylation at C-l7 according to known procedures, e.g. as described in Example 7 B.

The 6-alkoxy-16-alkylidene-17a-hydroxy-l,4,6-pregnatriene-3,20-dione intermediates are conveniently prepared basic hydrolysis of the corresponding 17a-lower alkanoate ester derivatives which in turn are prepared from the corresponding 1,2-dihydroprogesterones of our invention (i.e. those compounds wherein Z or Z is CH -CH by known chemical dehydrogenating methods, e.g. those utilizing 2,3-dichloro-5,6-dicyanobenzoquinone in benzene or selenium dioxide in tert.-butyl alcohol, or by employing microbiological techniques such as by the action of Bacillus sphaericus or Corynebacterium simplex. For example, 6 methoxy-l6-methylene-l7oz-acetoxy-4,6-preg nadiene-3,20-dione (a compound of Formula I wherein Z is -CH CH upon treatment with 2,3-dichloro-5,6- dicyanobenzoquinone yields the intermediate 6-methoxy- 16 methylene-17a-acetoxy-1,4,6-pregnatriene-3,20-dione which upon alkaline hydrolysis yields 6-methoxy-16- methylene-17ot-hydroxy-l,4,6-pregnatriene-3,20-dione.

The following experiments illustrate in detail some of the compounds and processes for their preparation which constitute this invention. This invention is not to be construed as limited in scope thereby since it will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention.

EXAMPLE 1 6-methoxy-l6-methylene-17a-hydroxy-4,6- pregnadiene-3,20-dione To a solution of l6-methylene-l7ot-hydroxy-4-pregnene- 3,20-dione (34.2 g.) in methanol (1.7 liters) heated to reflux temperature add 68.2 g. of cupric chloride hydrate CuCl -ZH O) and reflux and reaction mixture for one hour. Cool the reaction mixture, filter and then concentrate the filtered reaction solution in vacuo to a volume of about 300 ml. and pour the foregoing concentrate into 3 liters of saturated aqueous ammonium chloride. A precipitate comprising 6-methoxy-16-methylene-17whydroxy4,6-pregnadiene-3,20-dione separates. Isolate the precipitate by filtration, wash with water and partially dry by suction on the filter.

Purify by dissolving the 6-methoXy-l6-1nethylene-17ahydroxy-4,6-pregnadiene-3,20-dione in 680 ml. of methanol and stir for 15 minutes with 34 g. of zinc dust. Remove the zinc by filtration and boil the filtrate with 17 g. of Darco G-60. Filter the darco and add 400 ml. of water slowly. Cool the mixture to 5 C. and allow it to stand overnight. Filter the crystalline precipitate, wash with cold 50% methanol and dry to give 19 g. of 6- methoxy-16-methylene 17cc hydroxy 4,6 pregnadiene- 3,20-dione. M.P. l76l79C.; [oc] 61-6 (dioxane);

M 246; 302 m (em 8050; 10700) max.

NMR: 6 (ppm) TMS:0; 0.89 (C CH 1.12 (C CH 2.32 (C -CH 3.60 (C -OCH 5.11 (C- H); 5.11 and 5.31 (C CH 6.27 (C H).

1 1 EXAMPLE 2 6-methoxy-16-methylene-17a-acetoxy-4,6- pregn adiene-3 ,20-dione To a stirred suspension of 16-methylene-17a-acetoxy- 4 pregnene-3,20-dione (57.67 g.) in 2.88 liters of methanol at reflux temperature add 102.29 g. of cupric chloride hydrate (CuCl -2H O) reflux the reaction mixture with stirring for one hour, cool then filter and concentrate the filtrate in vacuo to a volume of about 600 ml. Pour the foregoing concentrate into 6 liters of saturated aqueous ammonium chloride and remove the resultant precipitate by filtration, wash with water and dry to yield 57 g. of product comprising 6-methoxy-16-methylene-17a-acetoxy- 4,6-pregnadiene-3,ZO-dione.

Purify by dissolving the product in 90 ml. of methanol and stirring for 5 minutes with 29 g. of zinc dust. Remove the zinc by filtration and treat the filtrate (hot) with darco, filter the darco and concentrate the filtrate to a volume of about 1.1 liters. Slowly add 80 ml. of water and allow the mixture to stand several hours at room temperature and then overnight at 5 C. Collect the resultant crystalline solid by filtration, wash with cold 50% aqueous methanol and dry at 70 C. Recrystallize from aqueous acetone (darco treated) to give 3.5 g. of 6- methoxy-16-methylene-17a-acetoxy 4,6 pregnadiene 3, 20-dione. M.P. 155159 C.; [a] l53.9 (dioxane);

) MeOH 24 303 (em 8350; 141400) Alternate process for the preparation of 6-methoxy-16- methylene-l7ot-acetoxy 4,6 regnadiene-3,20-dione (via the enol ether) The requisite starting compound, i.e. 3-ethoxy-16-methylene-17a-acetoxy 3,5 pregnadien-ZO-one is prepared according to known procedures from 16-methylene-l7aacetoxy-4-pregnene-3,20-dione utilizing ethyl-o-formate, concentrated sulfuric acid, anhydrous ethanol and dioxane.

To ml. of methanol add 103 mg. of 3-ethoxy-16- methylene-17u-acetoxy-3,5-pregnadien-20-one and 171 mg. of cupric chloride hydrate (CuCl -2H O). Reflux the reaction mixture for 1.5 hours, then distill the methanol in vacuo to a small volume. Pour the resultant slurry into water saturated with ammonium chloride. A precipitate comprising 6-methoxy-l6-methylene 17cc acetoxy-4,6- pregnadiene-3,20-dione separates. Filter, wash with water and dry, then purify by crystallization from aqueous methanol to give 62 mg. of 6-methoxy-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione.

EXAMPLE 4 Alternate procedure for the preparation of 6-methoxy-16- methylene-17ot-acetoxy 4,6 pregnadiene-3,20-dione via the enol ether) The requisite starting compound, i.e. 3,17OL-dl3C6tOXY- 16-methylene-3,S-pregnadien-ZO-one is prepared according to known procedures from 16,8-methyl-16a,17a-oxido-4- pregnene-3,20-dione by treatment with sulfosalicylic acid and acetic anhydride in toluene.

To 107 mg. of 3,17a-diacetoxy-16-methylene-3,5-pregnadien-20-one in 10 ml. of methanol add 171 mg. of cupric chloride hydrate (CuCl -2H O), reflux the reaction mixture for 1.75 hours then distill most of the methanol 12 in vacuo. Pour the resultant slurry into 20 ml. of saturated aqueous ammonium chloride and filter the resultant precipitate comprising 6-methoxy-16-methylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione. Wash with water and dry. Yield=82 mg.

EXAMPLE 5 6-metl1oxy-16-methylene-17a-hydroxy-1,4,6-pregnatriene- 3 ,20-dione (A) To 296 ml. of benzene add 7.4 g. of 6-methoxy-16- methylene-17a-hydroxy 4,6 pregnadiene-3,20-dione and 7.94 g. of 2,3-dichloro-5,6-dicyanobenzoquinone. Reflux the solution for 24 hours, cool, filter and distill the benzene in vacuo to a concentrate of about 50 ml. Place the concentrate on a chromatographic column packed with 350 g. of Florisil washed in hexane. Elute the column successively using hexane, ether, then ether containing increasing amounts of methylene chloride. Collect the eluates from the 10-30% methylene chloride in ether mixtures and evaporate the combined eluates to a residue. Crystallize the residue from ether to give 581 mg. of 6-methoxy-16- methylene-17a-hydroxy-1,4,6-pregnatriene-3,20-dione.

rmor; 235; 317 my, (em 13,900; 6,400)

nmr: 5 (p.p.n1.) (Cm-CH3); (C19- CH 2.32 (C -CH3); 3.62 (C OCH 4.98 (C H); 5.12 and 5.32 (C CH 6.25 (C H); 6.53 (G -H); 7.08 (C H).

(B) The compound of this example is also prepared as follows.

To a solution of 4.1 g. of 6-methoxy-16-methylene-17aacetoxy-1,6-bisdehydroprogesterone (prepared as described in Example 6A) in ml. of methyl alcohol add 5.25 ml. of 2-normal aqueous sodium hydroxide. Stir under an argon atmosphere at room temperature for 18 hours. Dilute the reaction mixture with 50 ml. of water then neutralize with acetic acid. Concentrate in vacuo to a crystalline slurry. Filter the crystalline solid, wash with water, and dry to give 3.7 g. of 6-methoxy-16-methylene- 17u-hydroxy-1,4,6-pregnatriene-3,20-dione.

EXAMPLE 6 6-methoxy-16-methylene-l7a-acetoxy-1,4,6-pregnatriene- 3 ,ZO-dione (A) Add 1.24 g. of 6-methoxy-16-methylene-17u-acetoxy-4,6-pregnadiene 3,20 dione and 1.02 g. of 3,2-dichloro-5,6-dicyanobenzoquinone to 49 ml. of benzene. Reflux for 24 hours, cool, filter, and distill the benzene in vacuo to a concentrate of a small volume. Pour the concentrate on to a chromatographic column containing 36 g. of hexane-Washed Forisil. Elute the column using ben zene followed by benzene containing increasing amounts of methylene chloride. Combine the eluates obtained from 20% to 75% mixtures of methylene chloride in benzene and evaporate to a residue. Crystalize the residue from aqueous methanol (darco treated) to give 550 mg. of 6- methoxy-16-methylene 17cc acetoxy-1,4,6 pregnatriene- 3,20 dione; M.P. -124 C.; [04],; 204.3 (dioxane);

W 235; 315 m (em 16,000; 9,375)

nmr: 6 (ppm) TMS=O; 0.81 (C -CH 1.21 (C (C OCH 4.96 (C H 5.49 and 5.60 (C CH 6.26 C H); 6.53 (C -H); 7.06 (C H).

In similar manner treat 6-methoxy-16-methylene-17acaprooxy-4,6-pregnadiene-3,20-dione with 2,3-dichloro- 5,6-dicyanobenzoquinone in benzene and isolate the resultant product in a manner similar to that described above to obtain 6-methoxy-l6-methylene 17a caprooxy-l,4,6- pregnatriene-3,20-dione.

(B) Alternatively the compound of this example is prepared as follows. To a solution of 2.1 g. of 6-methoxy-16- methylene-17a-hydroxy 1,4,6 pregnatriene-3,20-dione and 220 mg. of p-toluenesulfonic acid in 11 ml. of acetic acid cooled to 10 C. and under an argon atmosphere add dropwise over a 10 minute period 4.4 ml. of trifluoro- 13 acetic anhydride. Stir the mixture for one hour at room temperature then pour into water and separate by filtration the resultant product comprising 6-methoxy-16-methylene-17a-acetoxy 1,4,6 pregnatriene-3,20-dione then Wash with water and dry.

Purify by crystallization from aqueous methanol to give 6-methoxy-16-methylene 17oz acetoxy-1,4,6-pregnatriene-3,20-dione.

In similar manner, by substituting for acetic acid other lower alkanoic acids such as butyric acid and valeric acid, there is obtained the corresponding 17-lower alkanoate derivative, e.g. 6-methoxy-l6-methylene-17a-butyroxy-1,4, 6-pregnatriene-3,20-dione, respectively.

EXAMPLE 7 1u,2a-cyclomethylene-6-methoxy-16-methylene-17aacetoxy-4,6-pregnadiene-3,20-dione (A) 1a,2a-cyclomethylene-6-methoxy 16 methylene- 17a-hydroxy-4,6-pregnadiene-3,20-dionez Add 1.32 g. of trimethylsulfoxoniurn iodide and 144 mg. of sodium hydried (50% dispersion in oil) to 21 m1. of dimethylsulfoxide and stir under an argon atmosphere for 2 hours at room temperature then add 1.104 g. of 6-methoxy-16- methylene-17a-hydroxy-1,4,6-pregnatriene-3,20-dione and continue stirring for 18 hours. Pour the reaction mixture into water, acidify with hydrochloric acid, filter the resultant precipitate comprising la,2a-cyclomethylene-6- methoxy 16 methylene-17a-hydroxy-4,6-pregnadiene-3, 20-dione, wash with water and dry. Yield=-1.06 g.

Purify by crystallization from acetone-hexane to give 1a,2ot-cyclomethylene-6-methoxy 16 methylene 17ahydroxy-4,6-pregnadiene-3,20-dione. M.P. 224227 C; [a] 97.5 (dioxane);

MER 242 and 302 my (em 8,250 and 12,400)

nmr: 6 (p.p.m.) TMIS=O; 0.090 (C -CH3); 1.21 (C -CH 2.32 (C -CH 3.5a (c -00113); 5.00 (C ,H); 5.12 and 5.32 (C =CH 6.12 (C H).

(B) 1a,2wcyclomethylene-6-metl1oxy 16 methylene- 17a-acetoxy-4,6-pregnadiene-3,20-dione: To a solution of 2.2 g. of :,20z cyclomethylene-6-methoxy-16-methylene-17a-hydroxy-4,6-pregnadiene-3,20-dione and 220 mg. of p-toluenesulfonic acid in 11 m1. of acetic acid under an argon atmosphere and at 10 C. and dropwise over a 10 minute period 4.4 ml. of trifluoroacetic anhydride. Stir the mixture for one hour at room temperature then pour into water. A precipitate forms comprising 104,2- cyclomethylene-6-methoxy-16-methylene 171x acetoxy- 4,6-pregnadiene-3,20-dione. Separate by filtration, wash with Water then dry.

Purify the chromatographing on a column containing 30 g. of hexane-washed Florisil. Elute the column using hexane followed by hexane with increasing amounts of ether. Combine the eluates from 25 %-50% ether-hexane mixtures. Evaporate the combined eluates to dryness and recrystallize the resultant residue from aqueous methanol to give 707 mg. of 1a,2a-cyclomethylene-6-methoxy-16- methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione; M.P. 196-200 C.; [ot] 8.6 (dioxane):

AMeOH 240; 301 mu (em 8,400; 12,900)

(C) Alternatively the compounds of Example 7B, is also prepared by treating 6-methoxy-16-methylene-17aacetoxy-1,4,6-pregnatriene-3,20-dione with trimethylsulfoxonium iodide and sodium hydride in dimethylsulfoxide in the manner described in above procedure 7A. Isolate and purify the resultant product in a manner similar to that described to obtain 1u,2a-cyclomethylene-6-methoxy- 1G-methylene-17ot-acetoxy4,6-pregnadiene-3,20-dione.

EXAMPLE 8 6-methoxy-16-methylene-17a-propionoxy-4,6- pregnadiene-3 ,20-dione 6-ethoxy-16-methylene-17a-acetoxy-4,6-pregnadiene- 3,20-dione (A) 6-keto-16-methylene-17uacetoxy-4-pregnene-3,20- dione: Add 6 g. of 6-methoxy-16-methy1ene-17a-acetoxy- 4,6-pregnadiene-3,20-dione and mg. of p-toluenesulfonic acid to 60 ml. of 80% aqueous acetic acid. Heat the reaction mixture at reflux temperature for one hour then add slowly 15 0 ml. of water. Set aside the reaction mixture at room temperature to crystallize, then chill to 5 C. for several hours. Filter the resultant precipitate comprising 6-keto-16-methylene-17m-acetoxy-4-pregnene-3,20- dione, wash with water then dry in vacuo. Yield=3.06 g. Purify by recrystallization from aqueous methanol to give 1.6 g. of 6-keto-16-methylene-17u-acetoxy-4-pregnene-3,20-dione; M.P. 2062l0 C.; [a] 151.0 (dioxane);

MeOH max.

250 my (em 10,300)

Similarly treat each of the following with p-toluenesulfonic acid in aqueous acetic acid in the manner described above: i

6-methoxy-16-methylene-17 m-valeroxy-4,6-pregnadiene- 3 ,20-dione,

6-methoxy-1 6-methy1ene- 17 u-caprooxy-4,6-pregnadiene- 3 ,20-dione,

6-methoxy-16-methylene-17a-acetoxy-1,4,6-pregnatriene- 3 ,20-dione, and

111,2 a-cyclomethylene- 6-methoxy-16-methylenecacetoxy-4,6-pregnadiene-3 ,20 dione.

Isolate and purify the resultant products in a manner similar to that described hereinabove to give respectively 6-keto-16-methylene-17a-valeroxy-4-pregnene-3 ,20-dione, 6-keto-16-methylene-17ot-caprooxy-4-pregnene 3,20-dione, 6-keto-1 6-methylene- 17a-acet0xy-1,4-pregnadiene- 3 ,20-dione and 1a,2x-cyc1omethylene-6-keto-16-methylene-17a-acetoxy- 4-pregnene-3,20-dione.

(B) Stir together for 48 hours a solution of 1 g. of 6-keto-16-methylene-4-pregnene-3,20-dione in 30 ml. of ethyl alcohol and 1.5 ml. of boron trifluoride etherate. Pour the reaction mixture into aqueous sodium bicarbonate solution and collect the resultant precipitate by filtration, Wash with water and dry to give 903 mg. of 6-ethoxy-1o-methylene-17ot-acetoxy-4,6 pregnadiene 3, 2O dione [a] 6.9 dioxane. nmr: 6 (p.p.m.) TMS=O; 0.80 (C CH3); 1.15 (C -CH3); 1.32 (C OCH CEQ); 2.15 (C -CH 3.78

c -ocg crr 5.09 (C -H); 5.48 and 5.61 (C =CH 6.35 (Cy-H);

A 248; 303 m (em 8,750; 11,500)

Similarly treat each of the following 6-keto compounds with boron trifluoride in ethanol in the manner described hereinabove.

6-keto-16-methylene-l7a-valeroxy-4-pregnene-3,20dione,

6-keto-16-methylene-17ot-caprooxy-4-pregnene-3 ,20-dioue,

6-keto-16-methylene-l7rx-acetoxy-1,4-pregnadiene-3,20-

dione, and

1a,2a-cyclomethylene-6-keto-l6-methylene-17ot-acetoxy- 4pregnene-3 ,20-dione.

Isolate and purify the resultant products in the manner described hereinabove in Example 9B to give, respectively EXAMPLE 10 16-butylidene-17a-acetoxy-4-pregnene-3 ,ZO-dione and 16-ethylidene- 1 7ot-acetoxy-4-pregnene-3 ,20-dione (A) 160t-I'1-bIllIy1 5 pregnen-3fi-ol-20-one 3-acetate and l6a-ethyl-5-pregnen-3fi-ol-20-one 3-acetate: To a Grignard reagent prepared from 10.5 g. of butyl iodide and 1.8 g. of magnesium in 40 ml. of ether and containing 20 mg. of cupric chloride add a solution of 3.6 g. of 5,16- pregnadien-Sfl-ol-ZO-one 3-acetate in 20 ml. of dry toluene. Distill the reaction mixture until a vapor temperature of 100 C. is reached, then stop the distillation and maintain the reaction temperature at 100 C. for 5 hours. Cool the mixture, pour onto ice and an aqueous solution of ammonium chloride and separate the resultant solvent layers. Distill the organic layer in vacuo to a residue, chromatograph on Florisil with hexane. Elute the column with hexane followed by increasing amounts of ether-in hexane. Combine the eluates ranging from ether-inhexane and evaporate to a residue. Re-esterify this residue by dissolving in ml. of dry pyridine and 3 ml. of acetic anhydride and allow to stand at room temperature for 5 hours. Add water, filter the resultant precipitate and crystallize the precipitate from acetone-hexane to give 16a-n-butyl-5-pregnen-3B-ol-20-one 3-acetate.

In a similar manner treat 5,l6-pregnadien-3,B-ol-20-one 3-acetate with ethyl magnesium iodide and isolate the resultant product and re-esterify this product with acetic anhydride in pyridine to give l6u-ethyl-5-pregnen-3,B-ol- 20-one 3-acetate.

(B) 16a-n-butyl-17a-bromo-5-pregnen-3B-ol-20-one 3- acetate and 16ot-ethyl-17a-bromo-5-pregnen-3fi-ol-20-one 3-acetate: To 1 g. of 16a-n-butyl-5-pregnen-3fi-ol-ZO-one 3-acetate in 10 ml. of acetic acid add 2.1 molar equivalents of bromine in acetic acid. When the bromine color disappears add 0.5 g. of sodium iodide in 3 ml. of water. Warm the solution at C. for 20 minutes, cool and then dilute with water. Filter the resultant precipitate, wash with water, dry and crystallize from aqueous acetone to give 16a-n-butyl-17a-bromo-5-pregnen-3 6-01-20- one 3-acetate.

In similar manner treat 16iz-ethyl-S-pregnen-3B-o1-20- one 3-acetate with 2.1 equivalents of bromine in acetic acid followed by treatment of the resultant product with 0.5 g. of sodium iodide, then isolation and purification of 16 the final product in a manner similar to that described, to give 16a-ethyl-17a-bromo-5-pregnene-3B-ol-ZO-one 3- acetate.

(C) 16-n-butyl-5,16-pregnadien-3p-ol-20-one 3-acetate and 16-ethyl-5,16-pregnadien-3[3-ol-20-one B-acetate: Add 1 g. of 16an-butyl-17a-br0rno-5-pregnen-3fi-ol-ZO-one 3- acetate to 20 ml. of dimethylformamide and heat the solution under a nitrogen atmosphere at reflux temperature for 3 hours. Cool the reaction mixture, then pour into ice Water containing excess hydrochloric acid and extract with methylene chloride. Wash the combined methylene chloride extracts with water, then dry over magnesium sulfate and evaporate to a residue. Chromatograph this residue over Florisil eluting with hexane followed by increasing amounts of ether-in-hexane. Combine the eluates ranging from 10% ether-in-hexane to 30% ether-in-hexane and evaporate to a residue. Crystallize the residue from methylene chloride-hexane to give l6-n-butyl-5,16 pregnadien-3B-ol-20-one 3-acetate.

In a similar manner treat 16ot-ethyl-17abromo-5-pregnen-3fi-ol-20-one 3-acetate with dimethylformamide and isolate and purify the resultant product in a manner similar to that described to give 16-ethyl-5,l6-pregnadien-3flol-20-one 3-acetate.

(D) l6fl-n-butyl-16a,17a-oxido 5 pregnen-3,8-ol-20- one and 16fi-ethyl-16a,17a-oxido 5 pregnen-3p-ol-20- one: To a solution of 3 g. of 16-n-butyl-5,l6-pregnadien- 3fl-ol-20-one 3-acetate in ml. of methnol at approximately 15 C. add 3 ml. of 4-N-sodium hydroxide followed by 6 ml. of 30% hydrogen peroxide. Allow the mixture to remain at approximately 5 C. for 18 hours. Pour the reaction solution into 500 ml. of water and separate the resultant precipitate by filtration, then dry and crystallize from acetone-hexane to give 16f3-n-butyl-16a, 17a-oxido-5-pregnen-3p-ol-20-one.

('E) 16,8-n-butyl-16a,17a-oxido-4-pregnene-3,20 dione and 16B-ethyl-16a,17a-oxido-4-pregnene-3,20-dione: Dissolve 2.5 g. of 16fi-n-butyl-16a,17a-oxido-5-pregnen-3 fi-0l- 20-one in 172 ml. of toluene. Distill about 17 ml. of toluene then add 37.5 ml. of freshly distilled cyclohexanone followed by a solution of 1.25 g. of aluminum isopropoxide in dry toluene added dropwise over a fiveminute period. Reflux the solution for one hour under a Dean Stark trap then add cautiously 60 m1. of water, then azeotrope off the water. Cool the solution, filter and steam distill the filtrate. Filter the suspension left away steam distillation and wash the solid residue with water, dry and crystallize from isopropyl ether to give 16/3-nbutyl-16a,l7a-oxido-4-pregnene-3,20-dione.

In a similar manner treat -ethyl-16a,17u-oxido-5- pregnene-3,20-dione with aluminum isopropoxide in the presence of cyclohexanone to obtain l6,B-ethyl-16a,17moxido-4-pregnene-3,ZO-dione.

(F) 16-n-butylidene-l7a-hydroxy 4 pregnene-3,20- dione: Add 0.6 g. of 16fl-n-butyl-16a,17a-oxido-4-pregnene-3,20-dione to 17 ml. of acetic acid, warm the solution to 35 C. then add 0.17 ml. of a 10% solution of hydrobromic acid in acetic acid. Maintain the reaction mixture at approximately 35-45 C. for 20 minutes, then dilute with 20 ml. of Water. Separate the resultant precipitate by filtration and wash the residue with water, dry at 60 C. and crystallize from acetone to give 16-n-butylidene-17ahydroxy-4-pregnene-3,20-dione.

(G) 16-n-butylidene-17a-acetoxy-4-pregnene-3 ,20-dione and 16-ethylidene-17a-acetoxy-4-pregnene-3,20-dione: In a manner similar to that described in Example 6B, treat each of 16-n-butylidene 17cc hydroxy-4-pregnene-3,20- dione and 16-ethy1idene-17a-hydroxy 4 pregnene-3,20- dione with a mixture of acetic acid, p-toluenesulfonic acid and trifluoroacetic anhydride. Isolate and purify the resultant respective products in a manner similar to that described to give 16-n-butylidene-l7a-acetoxy-4-pregnene- 3,20-dione and 16-ethylidene-17a-acetoxy 4 pregnene- 3,20-dione, respectively.

In a similar manner in the above procedure if other lower alkanoic acids are substituted for acetic acid such 17 as 17-propionic acid and 17-caproic acid, there are obtained the respective propionic acid esters, namely l6-n-butylidene-17a-propionoxyl-pregnene-3,2O-dione, 16-n-butylidene-l7a-caprooxy-4-pregnene-3 ,ZO-dione, 16-ethylidene-17a-propionoxy-4-pregnene-3 ,ZO-dione, and 16-ethylidene-l7ot-caprooxy-4-pregnene-3,20-dione.

EXAMPLE 1 1 6 methoxy-16-n-butylidene-17u-acetoxy-4,6-pregnadiene- 3,20 dione and 6-methoxy-16-ethylidene-17x-acetoxy- 4,6-pregnadiene-3,20-dione (A) In a manner similar to that described in Example 2, treat each of 16-n-buty1idene-17a-acetoxy-4-pregnene- 3,20-dione and 16-ethylidene-l7a-acetoxy-4-pregnene-3,20 dione with cupric chloride hydrate in methanol at reflux temperature. Isolate and purify each of the resultant products in a manner similar to that described in Example 2 to obtain 6-methyl-16-n-butylidene-17a-acetoxy-4,6-pregnadiene-3,20-dione and 6 methoxy-16-ethylidene-l7u-acetoxy-4,6-pregnadiene-3,ZO-dione, respectively.

Utilize as starting steroid instead of the 17-acetate derivative named therein the following derivatives 16-n-butylidenel 7(x-propionoxy-4-pregnene-3,20-dione, 16-n-butylidene-l7a-caprooxy-4-pregnene-3,ZO-dione, 16-ethylidene-17or-prop'ionoxy-4-pregnene-3 ,20-dione, 16-ethylidenel 7a-caprooxy-4-pregnene-3,20-dione.

Isolate and purify the resultant respective products in a manner similar to that described to give respectively,

6-methoxy-l6-n-butylidene-l7a-propionoxy-4,6-

pregnadiene-3,20-dione, 6-methoxy-l6-n-butylidene-17a-caprooxy-4,6-

pregnadiene-3 ,20-dione, 6-methoxy-16-ethylidene-17 a-propionoxy-4,6-

pregnadiene-3,20-dione, 6-methoxy-16-ethylidene-l7u-caprooxy-4,6-

pregnadiene-3,20-dione.

(B) Treat each of 16 n butylidene-l7a-acetoxy-4 pregnene-3,20 dione and l6-ethylidene-17a-acetoxy-4- pregnene-3,20-dione With ethyl-o-formate, concentrated sulfuric acid and anhydrous ethanol and dioxane according to known procedures to obtain the following requisite starting compounds, i.e. 3 ethoxy-l6-n-butylidene-l7uacetoxy 3,5 pregnadien-ZO-one and 3-ethoxy-16-ethylidene-l7a-acetoxy-3,S-pregnadien-ZO-one.

In a manner similar to that described in Example 3, treat each of the three ethoxy enol ether derivatives prepared in the foregoing paragraph with cupric chloride hydrate in methanol. Isolate and purify the resultant respective products in a manner similar to that described to obtain respectively 6 methoxy-l6-n-butylidene-17aacetoxy-4,6-pregnadiene-3,20-dione and 6 methoxy-16- ethylidene-17a-acetoxy-4,6-pregnadiene-3,20-dione.

(C) The requisite starting compounds, i.e. 3,17a-diacetoxy-16-n-butylidene-3,S-pregnadien-ZO-one and 3,17ocdiacetoxy-l6-ethylidene-3,S-pregnadien-ZO one are prepared according to known procedures from 16,8-n-butyl- 1606,1706 oxido-4-pregnene3,20-dione and 16fi-ethyl-16a, 17a-oxido-4-pregnene-3,20-dione by treatment with sulfosalicylic acid and acetic anhydride in toluene.

In a manner similar to that described in Example 4, treat each of the three acetoxy enol esters prepared in the foregoing paragraph with cupric chloride hydrate in methanol and isolate and purify the resultant products to obtain respectively, 6-methoxy-16-n-butylidene-17a-acetoxy- 4,6-pregnadiene-3,20-dione and l6-methoxy-16-ethylidene- 17a-acetoxy-4,6-pregnadiene-3,20-dione.

(D) In a manner similar to that described in Example 1 treat each of 16-n-butylidene-l7a-hydroxy-4-pregnene- 3,20-dione and 16 ethylidene-l7u-hydroxy-4-pregnene- 3,20-dione with cupric chloride hydrate in methanol. Isolate and purify the resultant products in a manner similar to that described to obtain 6-methoxy-16-n-butylidene- 17a-hydroxy-4,6-pregnadiene-3,20-dione and 6-methoxyl6-ethylidene 17a hydroxy-4,6-prcgnadiene-3,ZO-dione, respectively.

In a manner similar to that described in Example 6B, treat each of 6-methoxy-16-n-butylidene-17ot-hydroxy-4, 6-pregnadiene-3,20- dione and 6-methoxy-16-ethylidene- 17a-hydroxy-4,6-pregnadiene-3,20-dione with acetic acid in the presence of p-toluenesulfonic acid and trifluoroacetic anhydride. Isolate and purify the resultant products in a manner similar to that described to yield 6-methoxy- 16-n-butylidene-l7a-acetoxy-4,6 pregnadiene-3,20-dione and 6 methoxy-l6-ethylidene 17a acetoxy-4,6-pregnadiene-3,20-dione, respectively.

EXAMPLE 12 6-ethoxy-16-n-butylidene 17a acetoxy-4,6-pregnadiene- 3,20-dione and 6-ethoxy-16-ethylidene-l7u-acetoxy-4,6- pregnadiene-3,20-dione (A) 16 n butylidene-l7a-acetoxy-4-pregnene-3,6,20- trione and 16 ethylidene-17a-acetoxy-4-pregnene-3,6,20- trione: In a manner similar to that described in Example 9A, treat each of 6-methoxy-16-n-butylidene-17a-acetoxy- 4,6-pregnadiene-3,ZO-dione and 6-methoxy-16-ethylidene- 17oz acetoxy-4,6-pregnadiene-3,20-dione with p-toluenesulfonic acid in aqueous acetic acid. Isolate and purify the resultant respective products in a manner similar to that described to obtain 16-n-butylidene-17a-acetoxy-4-pregnene-3,6,20-trione and l6-ethylidene-17a-acetoxy-4-pregnene-3,6,20-trione.

In the above described processes, by utilizing as starting compound the 17-caproate ester derivatives instead of the 17-acetate starting steroid, there are obtained the corresponding 6-keto-l7-caproate products, i.e. l6-nbutylidene-l7a-caprooxy-4-pregnene-3,6,20 trione and 16- ethylidene-l7oa-caprooxy-4-pregnene-3,6,20-trione, respectively.

(B) 6-ethoxy-l6-n-butylidene-17a-acetoxy 4,6 pregnadiene-3,20-dione and 6-ethoxy-16-ethy1idene-17oc-acetoxy-4,6-pregnadiene-3,20-dione: In a manner similar to that described in Example 9B treat each of 16-n-butylidene-17a-acetoxy-4-pregnene-3,6,20-trione and 16-ethylidene-17m-acetoxy-4-pregnene-3,6,20-trione with boron trifluoride etherate in ethyl alcohol. Isolate and purify the resultant respective products to give 6-ethoxy-16-n-butylidene-17a-acetoxy-4,6-pregnadiene-3,20 dione and 6-ethoxy-16-ethylidene-l7a-acetoxy 4,6 pregnadiene-3,20- dione.

By substituting the 17-caprooxy ester derivative in the above procedure in place of the 17-acetoxy derivative, there is obtained the corresponding l7-caproate product, i.e. 6 ethoxy 16-n-butylidene-l7a-caprooxy-4,6-pregnadiene-3,20-dione and 6-ethoxy-16-ethylidene-17a-caprooxy-4,6-pregnadiene-3,20-dione, respectively.

EXAMPLE l3 6 propionoxy l6 methylene 17a acetoxy 4,6- pregnadiene 3,20 dione and 6 butyroxy 16 methylene-17a-acetoxy-4,6-pregnadine-3,20-dione In a manner similar to that described in Example 9B, treat 16 methylene-l7ot-aoetoxy-4-pregnene-3,6,20-trione with boron trifiuoride etherate and propyl alcohol to obtain 6 propionoxy l6 methylene 17a acetoxy 4,6- pregnadiene-3,20-dione.

Similarly, in the manner described in Example 9B, treat 16 methylene 171x acetoxy 4 pregnene 3,6,20- trione with n-butyl alcohol and boron trifluoro etherate. Isolate and purify the resultant product in a manner similar to that described to obtain 6-butyroxy-16-methylene- 17a-acetoxy-4,6-pregnadiene-3,20-dione.

EXAMPLE l4 l6-methylene-17a-lower alkanoyloxy-21-cholor-4- pregnene-3,20-dione (A) methyl 1611,1711 oxido 21 chloro 4- pregnene-3,20-dione: To 0.5 g. of 16fl-methyl-l6a,17a-

1% oxido-21-iodo-4-pregnene-3,ZO-dione dissolved in 100 ml. of acetonitrile containing 1 ml. of water add a 50% aqueous solution of 1.7 g. of silver chloride. Warm the mixture at 3040 C. for four hours then filter and pour the filtrate into water. Filter the resultant solid comprising 16,8-methyl 16a,l7u oxido 21 chloro 4 pregnene- 3,20-dione.

(B) 16 methylene 1704 lower alkanoyloxy 21- chloro-4-pregnene-3,20-dione: Bubble argon gas through a solution of l g. of 16fi-methyl-l6a,l7ot-oxido-21-chloro- 4-pregnene-3,20-dione in ml. of acetic acid then under anhydrous conditions add 2 ml. of trifiuoroacetic anhydride. Heat the solution at 8095 C. for about an hour then pour into ice water and extract the resultant mixture with methylene chloride. Combine the organic extracts then in turn wash the organic extracts with 3% aqueous potassium carbonate and finally with water. Dry the methylene chloride solution over magnesium sulfate, filter and evaporate to a residue. Triturate the residue with acetoneisopropyl ether and filter the resultant solid to give 16- methylene-l7a-acetoxy-21-chloro-4-pregnene-3,20-dione.

By carrying out the above procedure in other lower alkanoic acids, e.g. propionic acid and caproic acid instead of acetic acid, there is obtained the corresponding 17-propionate and 17-caproate, respectively, i.e. l6-methylene-lh-propionoxy 21 chloro 4 pregnene 3,20- dione and 16 methylene 17cc caprooxy 21 chloro-4- pregnene-3,20-dione.

(C) Alternatively, the compounds of this example are prepared as follows: Treat lfi-methylene-17ot-hydroxy-2l iodo-4-pregnene-3,20-dione with silver chloride in moist acetonitrile in a manner similar to that described in Example 14A. Isolate and purify the resultant product in a similar manner to obtain l6-methylene-l7tx-hydroxy-2lchloro-4-pregnene-3,20-dione.

In a manner similar to that described in Example 6B treat 16 methylene 17oz hydroxy 21 chloro 4- pregnene-3,20-dione with acetic acid in the presence of p-toluenesulfonic acid and trifiuoroacetic anhydride under an Argon atmosphere and isolate and purify the resultant product to obtain 16-methylene-l7a-acetoxy-2l-chloro-4- pregnene-3,20-dione.

By substituting other lower alkanoic acids, e.g. butyric acid and valeric acid for acetic acid in the foregoing procedure, there is obtained the corresponding 17a-butyroxy and 17a-valeroxy derivatives, e.g. l6-methylene-17a-butyroxy 21 chloro 4 pregnene 3,20-dione and 16- methylene-17a-valeroxy-2l-chloro-4-pregnene-3,20-dione.

EXAMPLE l5 6-methoxyl 6-methylene-l7a-lower alkanoyloxy-2 l halogeno-4,6-pregnadiene-3 ,20-dione (A) 6 methoxy 16 methylene 170a lower alkanpyloxy-21-fluoro-4,6-pregnadiene-3,20-dionez In a manner similar to that described in Example 2, treat each of 16- methylene 17a -acetoxy 21 fluoro 4 pregnene-3,20- dione, 16 methylene 17cc caprooxy 21 fluoro 4- pregnene-3,20-dione and 16-methy1ene-l7a-propionoxy- 21-fiuoro-4-pregnene-3,20-dione with cupric chloride hydrate in methanol. Isolate and purify each of the resultant products in a manner similar to that described ,to give respectively 6 methoxy 16 methylene 17a acetoxy- 21-fluoro-4,6-pregnadiene-3,20 dione, 6 methoxy 16- methylene 17a caprooxy 21 fluoro 4,6 pregadiene- 3 ,20-dione and 6-methoxyl 6-m ethylenel 7ce-p10pi0I1OXY- 2l-fluoro-4,6-pregnadiene-3,20-dione.

(B) 6 methoxy 16 methylene l7a-lower alkanoyloxy 21 chloro 4,6 pregnadiene 3,20 dione: In a manner similar to that described in Example 2 treat each of 16 methylene 17a acetoxy 2l-chloro-4-pregnene- 3,20-dione, l6 methylene 17cc caprooxy 21 chloro- 4-pregnene-3,20-dione, 16 methylene 17cc valeroxy-Zlchloro-4-pregnene-3,20-dione and 16 methylene 170cbutyroxy-21-chloro-4-pregnene 3,20 dione with cupric chloride hydrate in methanol. Isolate and purify the resultant respective products to give 6-methoxy-16-methylene 170a acetoxy 21 chloro 4,6- pregnadiene-3,20- dione, 6 methoxy l6 methylene 17a caprooxy 21- chloro-4,6-pregnadiene-3,20-dione, 6 methoxy 16-methylene 17m valeroxy 21 chloro 4,6 pregnadiene- 3,20-dione and 6-methoxy-l6-methylene 17a butyroxy- 21-chloro-4,6-pregnadiene-3,20-dione, respectively.

(C) Alternatively, the compounds of this example are prepared as follows: In a manner similar to that described in Example 2, treat each of 16-methylene-17ahydroxy-Z1-fluoro-4-pregnene-3,20-dione and 16-methylene-17u-hydroxy-2 l-chloro 4 pregnene-3,20-dione with cupric chloride hydrate in methanol. Isolate and purify the resultant product in a manner similar to that described to give 6-methoxy-l6-methylene-l7ot-hydr0xy-21-fiuoro-4, 6-pregnadiene-3,20-dione and 6-methoxy-16-methylene- 170a hydroxy 21 chloro 4,6 pregnadiene 3,20- dione, respectively.

In a manner similar to that described in Example 68, treat each of 6-rnethoxy-16-methylene-17a-hydroxy-2lfluoro 4,6 pregnadiene 3,20 dione and 6 methoxy- 16-methylene-17a-hydroxy 21 chloro 4,6 pregnadiene-3,20-dione with a lower alkanoic acid such as acetic acid and propionic acid in the presence of trifiuoroacetic anhydride and p-toluenesulfonic acid under an atmosphere of argon. Isolate and purify the resultant respective products to obtain 6-methoxy-l6-methylene-17u-acetoxy 21- fiuoro 4,6 pregnadiene-3,20-di0ne and 6-methoxy-16- methylene 17a. propionoxy 21 fluoro 4,6 pregnadiene 3,20-dione, 6-methoxy-l6-methylene-l7a-acetoxy- 2l-chloro-4,6-pregnadiene-3,20-dione and 6 methoxy-16- methylene-17a-propionoxy-2l-chloro 4,6 pregnadiene- 3,20-dione, respectively.

EXAMPLE 16 6-methoxy-l6-ethylidene-17ot-acetoxy-21-halogeno- 4,6-pregnadiene-3 ,ZO-dione (A) ethyl-16a,l7a-oxido-4-pregnene-3,ZO-dione: The compound of this example is prepared from 5,16- pregnadiene-BfB-ol-ZO-one S-acetate according to known procedures as follows.

Treat 5,16-pregnadiene-3,B-ol-ZO-one S-acetate in toluone with ethyl magnesium iodide followed by subsequent acetylation at C-3 of the resultant product by treatment with acetic anhydride in dry pyridine to give l6oc-6thYl-5- pregnene-3B-ol-20-one S-acetate. Brominate at C-17 by treatment with bromine in acetic acid to give 16uethyl l7ot-bromo-5-pregnen-3fl-ol-ZO-one 3-acetate, Treat the foregoing 16a-ethyl-17a-bromo derivative with dimethylformamide according to known procedures to yield 16- ethyl-S,16-pregnadiene-3,6-ol-20-one 3-acetate which, upon treatment with alkaline hydrogen peroxide utilizing known methods produces 16,8-ethyl-l6a,l7or-oxido-4-pregnene-3, 20-dione.

('B) 165 ethyl-16a,17a-oxido-21-iodo-4-pregnene-3,20- dione: To 0.5 g. of 16,8-ethyl-16u,17a-oxido-4-pregnene- 3,20-dione in 5.6 ml. of tetrahydrofuran and 3.4 ml. of methanol, add 0.75 g. of finely ground calcium oxide and 0.75 g. of iodine. Allow the reaction mixture to stand for about 1.5 hours during which period the initial dark brown color slowly changes to pale yellow. Dilute the reaction mixture with methylene chloride, filter and wash the filtrate successively with an aqueous solution of 3% sodium iodide then 4% sodium thiosulfate and finally with water alone. Then evaporate the washed filtrate to a residue comprising 16/? ethyl-16a,17u-oxido-21-iodo-4-pregnene-3,20-dione. Purify by crystallization from acetone/ hexane.

(C) 165 ethyl-16a,17or-oxido-2l-fiuoro-4-pregnene-3,- 20-dione and 165-ethyl-16u,17a-oxido-21-ch1oro-4-preg nene-3,20-dione: In a manner similar to that described in Example 14A, treat 16fi-ethyl-16m,17x-oxido-2l-iodo-4- pregnene-3,20-dione with silver fluoride in moist acetonitrile to obtain l6fi-ethyl-l6ot,l7ot-oxido-2l-fiuoro-4-pregnene-3,20-dione.

In similar manner treat 1(SB-ethyl-16u,17m-oxido-21- iodo-4-pregnene-3,20-dione with silver chloride in moist acetonitrile according to the procedure of Eaxmple 14A to obtain 16B-ethy1-16a,17a-oxido-21-chloro-4-pregnene- 3,20-dione.

(D) 16 ethylidene l7a-acetoxy-21-halogeno-4-pregnene-3,20-dione: In a manner similar to that described in Example 14B, treat each of 16B-6thyl-160,170c-0XidO-21- fluoro 4 pregnene 3,20-dione and l6fl-ethyl-16ot,17aoxido-21-chloro-4-pregnene-3,20-dione with acetic acid and trifiuoroacetic anhydride. Isolate and purify the resultant respective products in a manner similar to that described to give l6-ethylidene-17a-acetoxy-21-fiuoro-4-pregnene-3,20-dione and 16-ethylidene-17a-acetoXy-2l-chloro- 4-pregnene-3,20-dione.

(E) 6-methoXy-l6-ethylidene-l7ot-acetoxy-21halogeno- 4,6-pregnadiene-3,20-dione: In a manner similar to that described in Example 2 treat each of 16-ethylidene-17aacetoxy-21-fluoro-4-pregnene-3,20-dione and 16-ethylidene-17a-acetoxy-21-chloro-4-pregnene-3,20-dione with cupric chloride hydrate in methanol. Isolate and purify the resultant respective products in a manner similar to that described to obtain -methoxy-16-ethylidene-17-uracet0xy- 2l-fluoro-4,6-pregnadiene-3,20-dione and 6-methoxy-l6- ethylidene 17a-acetoxy-21-chloro-4,6-pregnadiene-3,20- dione, respectively.

EXAMPLE 17 6-lower alkoxy-16-l0wer alkylidene-17a-acetoXy-21- halogeno-4,6-pregnadiene-3,20-dione (A) 16 -lower alkylidene-17ot-acetoxy-21-halogeno-4- pregnene-B,6,20-trione: In a manner similar to that described in Example 9A, treat each of the following with p-toluenesulfonic acid in 80% aqueous acetic acid.

6-methoxy-16-methylene-17oc-acetoxy-21-fluoro- 4,6-pregnadiene-3,ZO-dione,

G-methoxy-16-methylene-17ot-acetoxy-21-chloro-4,6-pregnadiene-3,20-dione,

6-methoxy-16-ethylidene-l7u-acetoxy-21-fluoro-4,6-pregnadiene-3,20-dione, and

6-methoxy-16-ethylidene-17a-acetoxy-2l-chloro-4,6-pregnadiene-3,20-dione.

Isolate and purify the resultant respective products in a manner similar to that described to obtain respectively 16-methylene-17a-acetoxy-21-fluoro-4-pregnene-3,6,20-

trione,

16-methylene-17a-acetoxy-21-chloro-4-pregnene-3,6,20-

trione,

16-ethylidene-l7a-acetoxy-2l-fluoro-4-pregnene-3,6,20-

trione, and

16-ethylidene-17ot-acetoxy-21-chloro-4-pregnene-3,6,20-

trione.

(B) 6-lower alkoxy-lG-lower alkylidene-17ot-acetoxy- 21-halogeno-4,6-pregnadiene-3,20-dione: In a manner similar to that described in Example 9B, treat each of the following with boron trifluoride etherate in ethyl alcohol.

16-methy1ene-17a-acetoxy-21-fluoro-4-pregnene-3,6,20-

trione,

16-methylene-17a-acetoxy-21-chloro-4-pregnene-3,6,20-

trione,

1fi-ethylidene-17a-acetoxy-21-fluoro-4-pregnene-3,6-20- trione, and

16-ethylidene-17a-acetoxy-2l-chloro-4-pregnene-3,6,20-

trione.

Isolate and purify the resultant respective products in a manner similar to that described to obtain respectively 6-ethoxy-l 6-methylene-17ot-acetoxy-2l-fluoro-4,6-

pregnadiene-3 ,20-dione,

6-ethoxy-16-methylene-17a-acetoxy-21-chloro-4,6-pregnadiene-3,20-dione,

6-ethoxy-16-ethylidene-17a-acetoxy-21-fluoro-4,6-pregnadiene-3,20-dione, and

6-ethoxy-16-ethylidene-l7aacetoxy-2l-chloro-4,6-pregnadiene-3,20-dione.

Similarly, by treating each of the starting compounds listed hereinabove with boron trifiuoride etherate in nbutanol there are obtained the corresponding 6-butoxy compounds,

6-n-butoxy-16-methylene-17a-acetoxy-2l-fiuor0-4,6-

pregnadiene-3 ,ZO-dione,

6-n-butoxy-16-methylene- 17 a-acetoxy-Z 1-chloro-4,6-pregnadiene-3 ,20-dione,

6-n-butoxyl 6-ethylidene- 17u-acetoxy-2 l -fluoro-4,6-

pregnadiene-3,20-dione, and

6-n-butoxy-l6-ethylidene-17a-acetoxy-2 l-ch1oro-4,6-

pregnadiene-3,20-dione, respectively.

EXAMPLE 18 1a,2a-cyclomethylene-6-lower alkoxy 16-lower alkylidene 17a acetoxy 21 halogeno 4,6 pregnadiene- 3,20-di0ne (A) 6-lower alkoxy-lfi-lower alkylidene-lh-acetoxy- 2l-halogeno-1,4,6-pregnatriene-3,ZO-dione: In a manner similar to that described in Example 5, treat each of the following with 2,3-dichloro-5,6-dicyanobenzoquinone in benzene.

fi-methoxy-l6-rnethylene-17a-acetoxy-2l-fiuoro-4,6-

pregnadiene-3 ,20-di0ne,

6-ethoxyl 6-methylene-l 7u-acetoxy-2 l -fluoro-4,6-

pregnadiene-3 ,ZO-dione,

6-methoxy-16-methylene-l7a-acetoxy-2l-chloro-4,6-

pregnadiene-3 ,20-dione,

6-ethoxyl 6-methylene-17a-acetoxy-2 1-chloro-4,6-

pregnadiene-3 ,ZO-done,

6-methoxy-16-ethylidene-l7ot-acetoxy-2 l-fiuoro-4,6-

pregnadiene-3 ,20-dione,

6-ethoxyl 6-ethylidenel 7oc-2IC6IOXY-2 lfluoro-4,6-

pregnadiene-3 ,ZO-dione,

6-methoxy- 16-ethy1idene-1 7a-acetoxy-21-chloro-4,6-

pregnadiene-3 ,ZO-dione,

6-ethoxyl G-ethylidenel7u-acetoxy-2 l -chloro-4,6-

pregnadiene-3 ,ZO-dione.

Isolate and purify the respective products in a manner similar to Example 5 to obtain respectively,

6-methoxyl 6-methylene- 1 7a-acetoxy-2 l-fiuorol ,4,6-

pregnatriene-3 ,20-dione, 6-ethoxy-l6-methylene-l7ot-acetoxy-21-fiuoro-l,4,6-

pregnatriene-3,20-dione, 6-methoxy-l6-methylene-17a-acetoxy-2lch1oro-1,4,6-

pregnatriene-3 ,20-dione, 6-ethoxy-l6-n1ethylene-l7a-acetoxy-21-chl0r0-1,4,6-

pregnatriene-3 ,ZO-dione, 6-methoxy-16-ethylidenel7a-acetoxy-2 l-fluorol ,4,6-

pregnatriene-3 ,ZO-dione, 6-ethoxy-16-ethylidene-17x-acetoxy-21-fluoro-1,4,6-

pregnatriene-3 ,ZO-dione, 6-methoxy-16-ethylidene-17a-acetoxy-21-chloro-1,4,6-

pregnatriene-3 ,20-dione, 6-ethoxy-16-ethylidene-l7a-acet0Xy-2l-chloro-1,4,6-

pregnatriene-3,20-dione.

(B) 10:,20: cyclomethylene-G-lower alkoxy-lG-lower alkylidene 17a acetoxy 2l-halogeno-4,6-pregnadiene- 3,20-dione: In a manner similar to that described in Example 7a, treat each of the following pregnatrienes with trimethylsulfoxonium iodide and sodium hydride in dimethyl sulfoxide under an argon atmosphere.

6-methoxy-16-methylene-17ot-acet0xy-2l-fluoro-1,4,6-

pregnatriene-3 ,20-dione,

6-ethoxy-1G-methylene-17a-acetoxy-21-fiuoro-1,4,6-

pregnatriene-3,20-dione,

6-methoxy-16-methylene-17a-acetoxy-2l-chloro-1,4,6-

pregnatriene-3,20-dione,

6-methoxy-16-ethylidene-17o-acetoxy-21-fiuoro-1,4,6-

pregnatriene-3 ,20-dione,

6-ethoxy-16-ethylidene-17u-acetoxy-21-fiuoro-1,4,6-

pregnatriene-3,20-dione,

6-methoxy-16-ethylidene-l7a-acetoxy-21-chloro1,4,6-

pregnatriene-3 ,20-dione,

6-ethoxy-16-ethylidene- 17x-acetoxy-2 1-chloro-1,4,6-

pregnatriene-3 ,20-dione.

Isolate and purify the resultant respective products in a manner similar to that in Example 7A to obtain respectively,

1a,2ot-cyclomethylene-6-methoxy-16-methylene-17aacetoxy-21-fluoro-4,6-pregnadiene-3,20-dione,

1 a,2a-cyclomethylene-6-ethoxy- 1 6-methylene-17rx-acetoxy-21-fluoro-4,6-pregnadiene-3 ,20-dione,

1a,2a-cyclomethylene-6-methoxy-16-methylene-17rxacetoxy-21-chloro-4,6-pregnadiene-3,20-dione,

1a,2ct-cyclomethylene-6-ethoxy-16-methylene-17a-acetoxy-21-chloro-4,6-pregnadiene-3 ,20-dione,

111,2a-cyclomethylene-6-ethoxy-16-ethylidene-17aacetoxy-21-fluoro-4,6-pregnadiene-3,20-dione,

1 a,2a-cyclomethylene-6-methoxy-1fi-ethylidene- 170cacetoxy-21-chloro-4,6-pregnadiene-3 ,20-dione,

1a,2a-cyclomethylene-6-ethoxy-16-ethylidene-17aacetoxy-Z1-chloro-4,6-pregnadiene-3 ,20-dione.

PHARMACEUTICAL FORMULATIONS OF 6- METHOXY 16 METHYLENE 17a-ACETOXY- 4,6-PREGNADIENE-3,ZO-DIONE I.Tablet formulations Formula A (5 mg): Milligrams per tablet 6 methoxy 16 methylene-l7aacetoxy-4,6-

pregnadiene 3,20-dione 5.0 Starch, food grade 5.0 Lactose, USP (spray dried) 89.5

Magnesium stearate, USP 0.5

100.0 Formula B (25 mg):

6 methoxy 16 methylene 17a acetoxy- 4,6 pregnadiene 3,20-dione 25.0 Starch, food grade 10.0 Lactose, USP (spray dried) 164.0 Magnesium stearate, USP 1.0

Pass the steroid through. a high speed mill equipped with a 100 to 150 mesh screen. Blend the milled steroid with the starch in a suitable mixing vessel. Add an equal weight of the spray dried lactose to the blend and mix until uniform. Combine the resultant blend with the remainder of the spray dried lactose and mix until uniform. Charge the magnesium stearate with a portion of the active tablet mix and blend. Blend the magnesium stearate mix with the remaining active tablet base. Continue mixing until uniform. Compress to target weight (100.0 mg. for 5 mg. tablet and 200.0 mg. for 25 mg. tablet).

1I.Capsule formulation Formula: Milligrams per capsule 6 methoxy 16 methylene-17a-acetoxy-4,6-

pregnadiene-3,20-dione 5.0 Lactose, USP (spray dried) 292.0 Magnesium stearate, USP 3.0

24 Blend ingredients until uniformly mixed. Fill into hard gelatin capsule.

III.Parenteral suspension Formula A (5 mg): Milligrams per milliliter 6 methoxy 16 methylene-17u-acetoxy-4,6-

pregnadiene-3,20-dione 5.00 Methyl cellulose 15 cps., USP 0.05 Sodium citrate, dihydrate 1 6.00 Benzyl alcohol, NF 9.00 Methylparaben, USP 1.80 Propylparaben, USP 0.20 Water for injection, USP, q.s. ad 1.00

Formula B (25' mg):

6 methoxy 16 methylene-17a-acetoxy-4,6-

pregnadiene-3,20-dione 25.00 Methyl cellulose 15 cps., USP 0.25

Sodium citrate, dihydrate 30.00

Benzyl alcohol, NF 9.00 Methylparaben, USP 1.80 Propylparaben, USP 0.20 Water for injection, USP, q.s. ad 1.00

Charge 45 l. of water for injection into a suitable stainless steel vessel and heat to -90" C. With vigorous agitation, slowly sprinkle the methyl cellulose into the hot water (5 gm. for Formula A or 25 gm. for Formula B). Agitate until the methyl cellulose is thoroughly dispersed and wetted. Add approximately 30 l. of cold (0.5 C.) Water for injection. Cool the entire mixture to 8 C. Dissolve the sodium citrate (600 gm. for Formula A or 3000 gm. for Formula B) in enough water for injection to make 5 l.

' of solution. Slowly and with agitation add this solution to the cooled methyl cellulose solution. Dissolve the parabens (180 gm. of methyl and 20 gm. of propyl) in 900 gm. of benzyl alcohol which has been heated to 30 C. Charge this solution to the chilled methyl cellulose cellulose solution. Bring the resulting solution to l. with water for injection and agitate until uniform. In a sterile area, pass the batch through a sterile filter. Aseptically transfer about 3.5 l. of the sterile methyl cellulose solution to a separate container reserving the remainder of the batch in a sterile stainless steel mixing tank. Slurry the steroid in a sterile colloid mill with about 2 l. of the separated methyl cellulose solution and add the slurry to the solution in the mixing tank. Rinse the slurry container and the mill with the remaining 1.5 l. of reserved methyl cellulose solution and add the rinse to the mixing tank. Rinse the slurry container and mill with 2 l. of water for injection and add the rinse to the mixing tank. Adjust the volume in the mixing tank to l. with water for injection and agitate until uniform. The batch afi'ords 100 l. of sterile suspension having the proportions of Formula A or Formula B.

Although the invention has been described above in terms of 6 rnethoxy-16-methylene-17u-acetoxy-4,6-pregnadiene-3,20-dione as the essential active ingredient, other 6 alkoxy l6-lower alkylidene-lh-lower alkanoyloxy-6- dehydroprogesterones of our invention as defined by Formula I hereinabove may be used in the above formulations and may be used for the treatment of benign prostatic hypertrophy in a manner similar to that described for 6 methoxy 16 methylene 17a-acetoxy-6-dehydro-progesterone, the daily dosage of compound to be administered being dependent upon the severity of the patients condition and the relative anti-androgenic activity of the compound being administered with respect to the preferred 6 methoxy 16 methylene 17a-acetoxy-6-dehydroprogesterone of our invention.

We claim:

1. A compound having the following structural formula:

wherein R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine, and chlorine; Y is lower alkanoyloxy; and Z is a member selected from the group consisting of 2. A compound of claim 1 wherein X is hydrogen.

3. A compound of claim 1 wherein X is hydrogen and Z is "CH2CH2- 4. A compound of claim 1 wherein R and X are hydrogen and Z is --CH CH 5. A compound of claim 1 wherein R is methyl, R and X are hydrogen, said compound being a member selected from the group consisting of 6-methoXy-l6-methylene- 17a lower alkanoyloxy 4,6-pregnadiene-3,ZO-dione and 141,20; cyclomethylene 6 methoxy 16-methylene-17otlower alkanoyloxy-4,6-pregnadiene-3,20-dione.

6. A compound of claim 1 wherein R is methyl, R and X are hydrogen, Y is acetoxy, and Z is CH CH said compound being 6-methoxy-16-methylene-17a-acetoXy-4,6-pregnadiene-3,20-dione.

7. A compound of claim 1 wherein R is ethyl, R and X are hydrogen, Y is acetoxy and Z is -CH CH said compound being 6-ethoxy-16-methylene-17u-acetoxy- 4,6-pregnadiene-3,20-dione.

8. A compound of claim 1 wherein R is methyl, R and X are hydrogen, Y is acetoxy, and Z is 3 oi1 oH said compound being 1a,2ot-cyclomethylene-6-methoxy-l6- methylene-17ot-acetoxy-4,6-pregnadiene-3,20-dione.

9. A compound having the following structural formula:

CH X

CHR

wherein R is lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine, and chlorine; and Z is a member selected from the group consisting of CH CH CH=CH, and

9 -o'HcH- and when Z is -CH=CH-, the 17-lower alkanoate esters thereof.

x itm,

Z, Li

wherein R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine, and chlorine; Y is a member selected from the group consisting of hydroxy and lower alkanoyloxy; and Z is a member selected from the group consisting of CH CH CH=CH-, and

13. A compound according to claim 12 wherein R and X are hydrogen; Y is lower alkanoyloxy; and Z is CH CH said compound being l6-methylene-l7ot-lower alkanoyloXy-4-pregnene-3,6,20-trione.

14. A compound according to claim 13 wherein Y is acetoxy, said compound being 16-methylene-l7ot-acetoxy- 4-pregnene-3,6,20-trione.

15. The process for the preparation of -6-alkoXy-16- alkylidene-6-dehydroprogesterones having the following structural Formula I:

I OCH: I

wherein R is a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of hydrogen, fluorine and chlorine, Y is a member selected from the group consisting of hydroxy and lower alkanoyloxy, and Z is a member slected from the group comprising CH CH CH X wherein R X, Y and Z are as hereinabove defined and V is a member selected from the group consisting of lower alkyl and lower alkanoyloxy, with a reagent selected from the group consisting of cupric chloride and cupric bromide in methanol.

16. The process of claim 15 including the subsequent step of isolating the compound of Formula I thereby formed.

17. The process of claim 15 when said reagent is cupric chloride in methanol.

18. The process of claim 15 when carried out with a compound of Formula II.

19. The process of claim 15 wherein said 6-unsubstituted-16-lower alkylidene 17a lower alkanoyloxyprogesterone is l6-methylene-l7a-acetoxyprogesterone, said reagent is cupric chloride in methanol; said process being the preparation of 6-methoxy-16-methylene-l7a-acetoxy 4,6-pregnadiene-3,20-dione which comprises treating 16- methylene-l7a-acetoxyprogesterone with cupric chloride in methanol.

20. The process for the preparation of 6alkoxy-l6- alkylidene-6-dehydroprogesterones defined by the following structural Formula 1:

wherein R is a lower alkyl, X is a member selected from the group consisting of H, fluorine, and chlorine; Y is lower alkanoyloxy; and Z is a member selected from the group consisting of -C-H -CH CH=CH; and

which comprises treating a 6-keto progesterone defined by the following structural Formula II:

wherein R, X, Y, and Z are as herein defined, with boron trifiuoride in the presence of a lower alkanol.

21. The process of claim 20 including the step of isolating the compound of Formula I formed thereby.

22. The process of claim 20 wherein said alkanol is ethanol whereby is formed a 6ethoxy compound of Formula I.

23. The process of claim 20 wherein said starting compound is a -ketoprogesterone of Formula II wherein R and X are hydrogen, Y is acetoxy, and Z is and wherein said lower alkanol is ethanol, which comprises treating 6-keto-16-methylene-17a-acetoXy-4-pregnene-3,20-dione with boron trifiuoride in ethanol whereby is formed 6-ethoxyl6-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione.

24. The process of claim 20 including the step of preparing said 6-keto compound of Formula II by treating a 6-methoxy-16-alkylidene 17o: alkanoyloXy-6-dehydroprogesterone of the following formula:

CH X

on I \1/ OCH;

wherein R is a member selected from the group consisting of hydrogen and lower alkyl, X is a member selected from the group consisting of hydrogen, fluorine and chlorine, and Y is lower alkanolyloxy; with p-toulenesulfonic acid in aqueous acetic acid.

25. The process of claim 24 wherein R and X are hydrogen, and Y is acetoXy, said process comprising treat- 111g 6-methoxy-l6-methylene-17a-acetoXy-4,6-pregnadiene- 3,20-dione with p-toluenesulfonic acid in aqueous acetic acid, and treating the thereby formed 6-keto-16- methylene-17a-acetoxy-4-pregnene-3,20-dione with boron trifiuoride in ethanol, whereby is formed 6-ethoxy-l6- methylene-17wacetoXy-4,6-pregnadiene-3,ZO-dione.

26. The process of claim 15 wherein about four moles of said reagent selected from the group consisting of cupric chloride and cupric bromide are used per mole of said 6- unsubstituted-l6-lower alkylidene-l7u-lower alkanoyloxy progesterone selected from the group consisting of 16- alkylideneprogesterones of Formula II and the 3-en0l ethers and 3-enol esters thereof defined by Formula III.

References Cited UNITED STATES PATENTS 3,462,465 8/1969 Holden et al. 260-3974 3,466,371 9/1969 Wiechert et al. 424-240 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

PO-ww UNITED STATES PATENT sema- QERTIFECATE 0F ECEECN Patent No. 5,629,505 7 Dated December 23., 1.971

Inventor) Richard Rausser and Robert Tiberi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 8, lines 20 and 21, "oxide in a manner similar to that described herein'below. process aspect of our invention described hereinbelow. should read --oxide in a manner similar to that described in the third process aspect of our invention described hereinbelow. Column 10, line 70, J -6l-6 should read --[Ot 7 -6l. 6 Column 11, line 16, "98 ml. should read --900 m1. Column 11, line 25, "5 5 g. should read --55. 5 g. Column 11, line 66, ."via the enol ether)" should read --(via the'eno'l 'acylate)--. Column 15, line 55, 9T. 5" should read 7 +97, 5 Column 15 line M, "and dgopwise" should read --add ropwise- Column 15, line 52, "Purify the" should read --Purify by--. Column 15, line 65, '12. 2" should read --l. 22--. Column 15, line 25, r,6-pregnatriene" should read +,6-pregnadiene--. Column 15, line 25, l,6-pregnatriene" should read +,6pregnadiene-. Column 16., line "left away" should read --left after-w Column 17, line 19, "6-methyl" should read --6-methoxy--. Column 21, line 8, "l6B-ethyl': should read --l6 B-ethyl--.

. I 7 Claim 24, c01umn 28, line 48, "lower alkanolyloxy should read lower alkanoyloxy Signed and sealed this 22nd day of August 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK J Atte sting Officer Commissioner of Patents 

